The health effects and economic burden associated with cigarette smoke (CS) exposure are overwhelming. The primary health effects are associated with symptoms of Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema. Currently, there are no effective therapies to deter disease progression in COPD patients. Over the last several decades, research has primarily focused on pathologies attributed to oxidative stress and the proteolytic imbalance associated with macrophage and neutrophil functions. Although the significance of these leukocytes and their effector functions are well documented, the mechanisms that lead to their aberrant activation by CS are poorly understood. The goal of our laboratory is to investigate the pathways whereby CS exposure activates pulmonary leukocytes. In this project, we present compelling evidence for a role of the CLEC5A activating receptor in macrophage activation in COPD. Our preliminary studies reveal that CLEC5A, expressed on alveolar macrophage, plays an integral role in macrophage activation following CS exposure. We generated a Clec5a-deficient mouse strain that reveals an essential role for CLEC5A in macrophage activation and pulmonary injury following CS exposure. The Clec5a-deficient mice fail to develop the hallmark features of COPD including pulmonary inflammation, macrophage accumulation and airspace enlargement. Furthermore, using a novel CLEC5A receptor fusion protein and CLEC5A-expressing reporter cell line, we provide evidence that a unique, previously undiscovered ligand for CLEC5A is expressed on CS-exposed pulmonary epithelial cells. These findings suggest a novel mechanism that promotes airway inflammation and pathologies in response to CS exposure.